Diabetes is characterized by insufficiency of the pancreatic beta cells to maintain normoglycemia. In type 1 diabetes this is due to destruction of the beta cells by an autoimmune process, whereas in type 2 diabetes it is due to a combination of beta cell deficiency and peripheral insulin resistance.
What most textbooks of pathology describe as cell death is coagulative necrosis. This is an abnormal morphological appearance, detected in tissue examined under the microscope. The changes, which affect aggregates of adjacent cells or functionally related cohorts of cells, are seen in a variety of contexts produced by accident, injury, or disease. Among the environmental perturbations that may cause cell necrosis are oxygen deprivation (anoxia), hyperthermia, immunological attack, and exposure to various toxins that inhibit crucial intracellular metabolic processes. Coagulative necrosis is the classical form of cell change seen when tissues autolyze (digest themselves) in vitro.
Apoptosis is an active process of cellular self-destruction that is regulated by extrinsic and intrinsic signals occurring during normal development. It is well documented that apoptosis plays a key role in regulation of pancreatic endocrine beta cells. There is increasing evidence that in adult mammalians the beta cell mass is submitted to dynamic changes to adapt insulin production for maintaining euglycemia in particular conditions, such as pregnancy and obesity. The control of beta cell mass depends on a subtle balance between cell proliferation, growth and cell death (apoptosis). A disruption of this balance may lead to impairment of glucose homeostasis.
Apoptosis is also associated with diseases such as cancer, immunological disorders, and neurodegenerative disorders.
Published patent application WO 9310127 discloses proline boronic esters useful as DPP-IV inhibitors.
Published patent application WO 9515309 discloses amino acid 2-cyanopyrrolidine amides as inhibitors of DPP-IV.
Published patent application WO 9529691 discloses peptidyl derivates of diesters of alpha-aminoalkylphosphonic acids, particularly those with proline or related structures.
Published patent application WO 9819998 discloses N-(N′-substituted glycyl)-2-cyano pyrrolidines, in particular 1-[2-[5-Cyanopyridin-2-yl]amino]-ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728).
Published patent application WO 9925719 discloses sulphostin, a DPP-IV inhibitor prepared by culturing a Streptomyces microorganism.
Published patent application WO 9938501 discloses N-substituted 4-8 membered heterocyclic rings.
Geman utility models DE 29909208 U, DE 29909210 U, and DE 29909211 U disclose val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl-pyrrolidide, and fumar salts of isoleucyl-thiazolidide and isoleucyl-pyrrolidide.
Published patent application WO 9946272 discloses phosphoric compounds as inhibitors of DPP-IV.
Published patent applications WO 9967278 and WO 9967279 disclose DPP-IV prodrugs and inhibitors of the form A-B-C where C is either a stable or unstable inhibitor of DPP-IV.
Published patent application WO 0034241 and published U.S. Pat. No. 6,110,949 disclose N-substituted adamantyl-amino-acetyl-2-cyano pyrrolidines and N-(substituted glycyl)-4-cyano pyrrolidines respectively.
In WO 97/40832 is disclosed use of DPP-IV inhibitors for lowering the blood glucose level in mammals.